I. Field of the Invention
The present invention relates generally to the fields of oncology and cancer therapy. More particularly, it concerns the assessment of factors to predict the efficacy of an anti-hyperproliferative disease therapy.
II. Description of Related Art
Cancer is a leading cause of death in most countries, and the result of billions of dollars in healthcare expense around the world. It is now well established that a variety of cancers are caused, at least in part, by genetic abnormalities that result in either the overexpression of cancer causing genes, called “oncogenes,” or from loss of function mutations in protective genes, often called “tumor suppressor” genes. An example is p53—a 53 kD nuclear phosphoprotein that controls cell proliferation. Mutations to the p53 gene and allele loss on chromosome 17p, where this gene is located, are among the most frequent alterations identified in human malignancies. The p53 protein is highly conserved through evolution and is expressed, albeit at low levels, in most normal tissues. Wild-type p53 has been shown to be involved in control of the cell cycle (Mercer, 1992), transcriptional regulation (Fields and Jang, 1990; Mietz et al., 1992), DNA replication (Wilcock and Lane, 1991; Bargonetti et al., 1991), and induction of apoptosis (Yonish-Rouach et al., 1991; Shaw et al., 1992).
Various mutant p53 alleles are known in which a single base substitution results in the synthesis of proteins that have quite different growth regulatory properties and, ultimately, lead to malignancies (Hollstein et al., 1991). In fact, the p53 gene has been found to be the most frequently mutated gene in common human cancers (Hollstein et al., 1991; Weinberg, 1991), and mutation of p53 is particularly associated with those cancers linked to cigarette smoke (Hollstein et al., 1991; Zakut-Houri et al., 1985). The overexpression of p53 in breast tumors has also been documented (Casey et al., 1991). Interestingly, however, the beneficial effects of p53 are not limited to cancers that contain mutated p53 molecules. In a series of papers, Clayman et al. (1995) demonstrated that growth of cancer cells expressing wild-type p53 molecules was also inhibited by expression of p53 from a viral vector.
As a result of these findings, considerable effort has been placed into p53 gene therapy. Retroviral delivery of p53 to humans was reported some time ago (Roth et al., 1996). There, a retroviral vector containing the wild-type p53 gene under control of a beta-actin promoter was used to mediate transfer of wild-type p53 into 9 human patients with non-small cell lung cancers by direct injection. No clinically significant vector-related toxic effects were noted up to five months after treatment. In situ hybridization and DNA polymerase chain reaction showed vector-p53 sequences in post-treatment biopsies. Apoptosis (programmed cell death) was more frequent in post-treatment biopsies than in pretreatment biopsies. Tumor regression was noted in three patients, and tumor growth stabilized in three other patients. Similar studies have been conducted using adenovirus to deliver p53 to human patients with squamous cell carcinoma of the head and neck (SCCHN) (Clayman et al., 1998). Surgical and gene transfer-related morbidities were minimal, and the overall results provided preliminary support for the use of Ad-p53 gene transfer as a surgical adjuvant in patients with advanced SCCHN.
Advances in the understanding of the critical role of abnormal p53 function in tumor proliferation and treatment resistance provided the rationale for developing p53 gene therapies for SCCHN and other cancers (Hartwell and Kastan, 1994; Kastan et al., 1995; Edelman and Nemunaitis, 2003; Ahomadegbe et al., 1995; Ganly et al., 2000; Zhang et al., 1995; Clayman et al., 1995; Clayman et al., 1998; Clayman et al., 1999; Swisher et al., 1999; Nemunaitis et al., 2000; Peng, 2005). For example, ADVEXIN® (Ad5CMV-p53, INGN 201) is comprised of a replication-incompetent adenovirus type 5 vector containing the normal p53 tumor suppressor gene as its therapeutic component.
However, despite gene therapy successes, it is presently unclear why some patients respond to p53 and other therapies while others do not. There remains a need to identify specific patient subsets that will most benefit from this treatment.
Several clinical prognostic factors influencing response to a therapy and survival have been identified in patients with recurrent SCCHN (Argiris et al., 2004; Pivot et al., 2001; Recondo et al., 1991). Molecular biomarkers have more recently been used to predict prognosis. However, with respect to the use of p53 biomarkers to predict prognosis, the field is characterized by conflicting data with some studies indicating the ability of p53 biomarkers to predict outcomes (Recondo et al., 1991; Gallo et al., 1995; Mulder et al., 1995; Sarkis et al., 1995; Sauter et al., 1995; Stenmark-Askmalm et al., 1995; Matsumura et al., 1996; McKaig et al., 1998; Nemunaitis et al., 1991) while others indicate that p53 biomarkers do not predict patient outcomes (Kyzas et al., 2005). In fact, one of the largest studies in head and neck cancers, a meta-analysis combining the results of 42 studies involving 3,388 patients revealed no statistically significant correlation between p53 biomarker status and clinical outcome (Kyzas et al., 2005).
Hence, there is a need to properly define p53 biomarker profiles capable of more reliable prediction of patient outcomes to guide the appropriate use of current therapies and to evaluate the efficacy of new treatments.